On Wednesday 28 October I attended a half-day of a two-day conference on “expanded access” at the New York Academy of Science. Johnson & Johnson sponsored the event and I felt that what I saw was guided by their pharma influence.

“Expanded access” is a term referring to a pharma company’s provision of an experimental drug to be used for treatment of an individual in dire circumstances when that drug is likely to be efficacious and there are no other options. Historically, this has been an unlikely convergence of circumstances. There is only a small window when there is evidence that a drug is safe and effective but not enough evidence or review to bring a drug to market. During that small window, there are few cases when that drug’s administration to a patient could be argued as so critical as to merit special consideration including review at the federal government level. Assuming that an experimental drug exists and the ideal patient requests it, beyond that the patient has to demonstrate extraordinary understanding of the risk of using a pre-market drug and the pharma company has to be persuaded that it will not be damaged by likely outcomes – harm to the patient, excessive demands from other people wanting the drug through expanded access, and lawsuits from people who want the drug but cannot get it through expanded access. Now further assuming that patient understanding is demonstrated and the pharma company agrees, in the United States the government has to approve the dispensing of the drug. This rarely happened in the past. This conference talked about how this process can be hurried.

Presenters at the conference spoke with non-traditional premises behind expanded access, including these new ideas:

Nowadays it is more likely that researchers can predict drug effects and safety more quickly and accurately with less research

Patients are more informed and can make better decisions to choose to take experimental drugs

A more informed public is collectively making more informed decisions to request expanded access, and this society-wide trend should be addressed

At any given time now, there are more safe and effective drugs in legal limbo than there were in the past

The good clinical research practices developed in the 1960s are becoming an outdated legacy in the case of expanded access, and their pace of the development is increasingly becoming more distant from the public demand for reform

Demand for change is a patient demand and not encouraged in any direct or roundabout way by industry influence in pursuit of pharma industry profit

I challenge all of these ideas. Definitely none of them are orthodox, and my personal opinion is that there is not sufficient evidence to give wholehearted support to any of these ideas.

To the conference – it was titled “Pre-approval access: can compassion, business, and medicine coexist?” “Pre-approval”, “compassionate use”, “right-to-try”, and “expanded access” are terms used interchangeably. From the beginning the conference gave me the creeps because I felt that the word “ethics” ought to be more prominent in guiding the discussion. “Compassion” is ignorant and rash, “business” means profit in this context, and “medicine” sort of supposes ethics but as an insider to this I know that “medicine” in this context is taken to mean that the doctor is a script monkey who dispenses the drugs available when pressured by someone panicked by death and demanding life from the hapless doctor. The traditional doctor-patient relationship rarely can provide useful information to guide patient decisions outside of evidence-based medicine, which means that for this to work a patient must leave either get their drugs from someone other than their doctor or their doctor must approve or condone their patient taking drugs which no one understands. The most troublesome part of this is the money value in doing research with experimental drugs on sick people who are willing to sign away the traditional medical protections. I understand that people who are about to die anyway have less risk in taking strange drugs when their lives already are as bad as they can get, but that will not be the usual case. The more usual case will be people who are sick but have pleasures in life, and they might risk what health they have to entities who have money in mind first and patient needs in mind beyond that.

The narrative that comes from patient advocacy groups calling for expanded access is that there are valuable drugs in laboratories which are likely to be effective, and where it not for needless bureaucratic delay, then their doctor (or a clinical researcher, or a pharma company) could give them the drug which would surely save their life. People who are threatened with death are panicked, and people become bitter and emotional after watching their loved ones die even while they believe that bureaucracy keeps lifesaving drugs out of reach. The emotion is real, and the concept of a lifesaving drug is compelling. I get that story. What bothers me is how patients are getting the idea that the drugs they want are really lifesaving, or even likely to have any effect, when based on historical precedent there almost never is any reason to think that an experimental drug could be helpful.

The numbers are probably changing, but the way that I learned things, if 10,000 drug concepts are considered, not more than 1000 are tested in animals, 100 go to humans for safety testing, 10 are tested for efficacy, and at the end none of those 10,000 ideas go to market because only 1 in 100,000 drug concepts proves safety and efficacy in the end. Most scientists who are employed in drug research finding new drug candidates spend their careers never having a single success and only finding dead ends. It is not easy to develop a new drug. With the advent of computers and genetic testing, I anticipate that it will be easier to predict what effects drugs will have in certain people, but so far as I know, technology has not advanced to point where it is safe to advocate for reform because of trust in computer magic. I know that day will come, and it likely will come suddenly, but I do not think we are there yet.

In the expanded access model, the usual premise is that after safety testing (phase 1 research) there might be some reason to anticipate benefit from using the drug as a therapy before phase 2 or 3 research. Any clinical researcher would say that it is very unlikely to have this information, because in phase 1 research the doses are typically so low and short that the research would generate no insight into efficacy. Also in early studies the drug is only tested on healthy test subjects who have no disease, so since they have nothing to cure, there usually would not be proof that the drug could treat a sick person. Without evidence of safety and efficacy it is hard to argue for expanded access. I worry that somehow patients and advocacy groups get the idea that safety and efficacy evidence exists, and are making a demand for expanded access when they do not have good information about the likelihood that expanded access will not benefit them and unnecessary use of a drug is more likely to cause them harm. Other circumstances calling for expanded access might use data from phase 2 or 3 research, but usually, the largest time window is after phase 1, and also “expanded access” usually is not the term used to describe participation in a clinical trial like a modified phase 2 that checks some efficacy or a phase 3 trial which definitely would check efficacy in the traditional way.

The canonical case advocating for expanded access is the period from about 1985-1995 when people with AIDS organized as a community to get access to antiviral medications to treat HIV infection. The circumstances there were that a sufficiently large number of people all shared the same disease, and that HIV was an odd disease which left people healthy for about five years but then killed them around seven years from infection. It was an interesting set of circumstances – people with HIV could become aware of when they would likely die some years later and talk about what they as a community might like to do in response. The response was that they participated in a lot of clinical research and made commitments as a community to share drugs which showed efficacy. Because death was so certain and so predictable, the community’s members could make uniquely informed decisions about how much medical risk to take with which experimental drugs and in which doses. Likewise, the medical research community could be confident that their pool of research participants were well informed to an unprecedented extent. Research study participants even hijacked the clinical research process by lying to pharma companies about who was getting what drugs, circumventing the randomized clinical trial process, spoiling the research data, but thereby sharing lifesaving drugs among each other in individual sacrifice that was good for the entire community. Another strange circumstance about this was that, especially closer to 1995 at the advent of AZT, this really crazy set of events actually found a lifesaving drug which was highly effective quickly and was described as bringing people back to health even after they were bedridden at the end of life. It is a powerful story with lots of circumstances which could not apply in other cases because so much about HIV is different from other cases which call for expanded access. At this conference – and indeed, I expect at all conferences like this – the precedent of HIV and expanded access was invoked and I did not feel that the circumstances around researching and treating HIV/AIDS could be referenced as generally applicable to other uses of experimental drugs. It is sad when a few hundred people have an unusual medical condition that a drug might treat, but the size of the HIV epidemic, closeness of the community of people with HIV, obviousness of antiviral drugs as a research direction, the unprecedented huge amount of money poured indiscriminately into early HIV research and community organization, and predictability of the illness are not characteristics that other communities of people with a given disease will likely have. I also have my own bias that people who did activism in that era are heroes and I resent anyone trying to tap the social cache of that demographic, their work, and their sacrifices.

I worry that some of the demand for expanded access is an effect of the brainless machinations of the pharma industry, which is a driving force toward deeper access to more human test subjects who will give themselves more willingly at more personal and community risk for the benefit of corporate profit and with decreased liability to corporate reputation. It worries me that when a patient advocacy group demands expanded access, they also decrease the pharma company’s liability to protect the safety of individuals, communities, and taxpayers who cleanup medical harms. I am the biggest proponent of clinical research, but at the same time I always dislike that volunteer test subjects want to give their data and test results to “science” but instead this data is always captured by certain commercial interests and their very anti-science motivation to compete with other corporations by not sharing research data or insights so as to suppress the competition. I feel strongly that corporations themselves are choosing to avoid doing their fair part to meet the interest of health advocacy groups, and my own niche complaint is that they apply restrictive copyright over information which is supposed to be public but which they do not actually want patients and health advocates to easily access. I especially want information including basic company information, drug safety data, basic data about their clinical research (like the AllTrials request), and my special demand the informed consent documents. When I see corporations sponsor events like this that ask for the patients to give up some rights in exchange for benefits, I immediately look for what the corporation is also giving. From what I saw at this conference, I would say nothing – the corporation wants to assume no risk but to become more profitable, and among all of the things they could give to empower patients more, those things are not offered.

In the parts of this conference that I attended, I was not hearing anyone talk about the harms associated with increased use of experimental therapies which lack evidence of safety and efficacy. I heard much too much about the rights of individuals to choose to take the drugs they want and my interpretation of the rationale backing this was that people should be free as they like and they have the “right to try”.

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